CZ341492A3 - 4,13-dioxabicyclo(8.2.1)tridecene derivatives,process and intermediates for their preparation and medicaments in which said derivatives are comprised - Google Patents

Abstract

Ring-contracted N-demethyl-N-isopropylerythromycin A derivatives with gastrointestinally effective motilin-agonistic properties and the preparation thereof are described. <IMAGE>

Description

4,13-Dioxabicyclo {8.2.1} tridecenone derivatives, process and intermediates therefor and medicaments containing these compounds

Technical field

The present invention relates to novel N-substituted compounds 2 2 R, 3 R (2 R ', 3 R *), 6 R, 7 S, 8 S, 9 R, 1 OR 3 - (2', 3'-dihydroxypent-2'-yl) -7- ( 2,6-dideoxy-3-C-methyl-3-O-methyl-6-oxo-hexpyranose-1-oxy] -9- (3,4,6-trideoxy-3-amino-1 H-) D-xylo-hexopyranosyl) oxyl] -2,6,8,10,12-pentamethyl-4,13-dioxabicyclo [8.2.1] tridec-12-en-5-one having motilin-agonist properties and their acid addition salts, as well as pharmaceutical preparations containing these compounds and processes and intermediates for making the compounds. The compounds of the invention are N-desmethyl-N-isopropyl derivatives of ring-restricted erythromycin A.

BACKGROUND OF THE INVENTION

As is known, the antibiotic erythromycin A has, in addition to its antibiotic effects, also gastrointestinal side effects, which are undesirable in antibiotics. Among other things, it is a marked increase in contraction activity in the stomach and intestinal area with stomach and intestinal cramps, nausea and diarrhea.

Many attempts have been made to alter erythromycin A so as to obtain derivatives in which there would be virtually no antibiotic effect, but to maintain an effect affecting the motility of the gastrointestinal tract. EP-A-0 349 100 A2 discloses pharmaceutical preparations which contain, as a gastroprokinetic active substance, a ring-restricted erythromycin A derivative or its quaternary salts and which enhance gastric motility by a cholinergic mechanism.

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel ring-reduced erythromycin A derivatives which do not have antibiotic activity and have a beneficial effect on the gastrointestinal tract motility.

SUMMARY OF THE INVENTION

It has now been found that the new ring-restricted N-desmethyl-N-isopropyl derivatives of erythromycin A exhibit selective motilin-agonist properties, stimulate gastrointestinal tract motility in a favorable manner, and exert an enhanced effect on the lower Oesophagus Sphincter tone. Because of their effect profile, the compounds of the invention are suitable for the treatment of motility disorders in the gastrointestinal tract, while being well tolerated.

Accordingly, the present invention provides novel [2R, 3R (2R ',

3R '), 6R, 7S, 8S, 9R, 10R] -3- (2', 3'-dihydroxypent-2'-yl) -2,6,8,10,12-pentamethyl-4,13-dioxabicyclo [8.2.1.0 &lt; 2,7 &gt; 1-Tridec-12-en-5-one of formula I

R ¹ l

N-CH (CH ₃ ) ₂ h ₃ c

HIM

H ₃ C

CH ₃ wherein R 1 is methyl or hydrogen, and their physiologically tolerable acid addition salts. In particular, a compound of formula I in which R ^{@ 3} represents methyl is advantageous.

Compounds of formula I may be obtained by compounds of [2R, 3R (2R ', 3R'), 6R, 7S, 8S, 9R, 10R] -3- (2 ', 3'-dihydroxypent-2'-yl) -2,6,8,10,12-Pentamethyl4,13-dioxabicyclo [8.2.1] tridec-12-en-5-one of formula II

introducing an isopropyl radical in a manner known per se and, if necessary, introducing a methyl radical R @ ³ into the compound of formula I in which R @ ³ represents a hydrogen atom, or methyl group is cleaved in the obtained compound of formula I in which R @ 3 is methyl. the residue R ^x and optionally converting the free compounds of formula I into their stable acid addition salts, or, (i) the acid addition salts are converted into the free compounds of formula I.

To introduce an isopropyl moiety, the compounds of formula II can be alkylated in a manner known per se. Preferably, the alkylation is carried out as reductive alkylation in a manner known per se by reacting a compound of formula II with acetone under reducing conditions. For example, the compounds of formula II may be reacted with acetone in the presence of a reducing agent, for example, a complex borohydride compound such as sodium cyanoborohydride, sodium triacetoxyborohydride or sodium borohydride. If desired, alkylation can be carried out. , _w . in particular those of the compounds of formula II in which R is methyl, may also be carried out by reaction with an isopropyl halide, in particular isopropyl iodide, or with isopropyl sulphate or isopropyl sulphonic acid ester. Suitably, the alkylation is carried out in an organic solvent which is inert under the reaction conditions.

For example, an excess of acetone may serve as the solvent for reductive alkylation. Also suitable as solvent are cyclic ethers, such as tetrahydrofuran or dioxane, aromatic hydrocarbons, such as toluene, or lower alcohols. Alkylation with ¹ mU to be performed at temperatures between room temperature and the boiling point of the solvent. The alkylation with an isopropyl derivative, for example an isopropyl halide such as isopropyl iodide, is preferably carried out in the presence of a base such as an alkali metal carbonate or a tertiary organic amine.

The compound of the formula I obtained, in which R @ 1 represents a hydrogen atom, can, if desired, be alkylated in a manner known per se to the corresponding N-methyl compound. The alkylation is carried out in a manner known per se by reaction with methyl halide or as reductive alkylation by reaction with formaldehyde under reducing conditions, and can be carried out, for example, under the conditions for alkylation of compounds of formula II.

If desired, a methyl radical can be cleaved off from a compound of formula I in which R @ ¹ is methyl. The demethylation can be carried out in a manner known per se by treating the compound with halogen, in particular iodine and / or bromine, in an inert solvent. in the presence of a suitable base. Suitable bases are, for example, alkali metal hydroxides and alkali metal salts of weak organic acids. The demethylation is preferably carried out in a slightly alkaline pH range, preferably below 9, to avoid a side hydrolytic reaction.

The compounds of the formula I can be isolated and purified from the reaction mixture in a manner known per se. The acid addition salts can be converted into the free bases in a conventional manner, which, if desired, can be converted into the pharmaceutically acceptable acid addition salts in a known manner. In order to avoid a side hydrolytic reaction, it is expedient to use an equivalent amount of acid to form salts.

Suitable pharmacologically acceptable addition salts of the compounds of the formula I are, for example, their salts with inorganic acids such as carbonic acid, hydrohalic acids, in particular hydrochloric acid, or with organic acids such as lower aliphatic mono- or dicarboxylic acids, such as maleic acid, fumaric acid, lactic acid, tartaric acid or acetic acid.

The starting compounds of formula XX have not been previously described in the literature. According to the invention, the compounds of formula II are valuable intermediates for the production of pharmacologically active compounds, for example compounds of formula I.

The compounds of formula II can be obtained by known methods starting from erythromycin A of formula III

Thus, erythromycin A can be first mono- or didemethylated by reaction with a halogen, preferably iodine, in an inert solvent in the presence of a suitable base in a manner known per se, for example by the method known from DE-OS 21 54 032. Suitable bases are, for example, alkali metal hydroxides, alkali metal carbonates and alkali metal salts with weak carboxylic acids, for example alkali metal acetates or propionates. Preferably, 1 to 5 equivalents of halogen are used based on the amount of demethylated erythromycin compound. The amount of the base is preferably selected so as to achieve a pH in the range of 5 to 9 in order to avoid side hydrolytic and alcoholytic reactions. Methanol, cyclic ethers such as dioxane or tetrahydrofuran, dimethylformamide or mixtures of the solvents mentioned with water are suitable as solvents. Dimethylation. This is conveniently carried out at temperatures between room temperature and 50 ° C. The reaction may be supported by irradiation with light, eg light with a wavelength above 290 nm from a mercury low pressure lamp with a filter of quartz or heat resistant glass,

R eg Pyrex. The reaction produces a monodemethylated or didemethylated product mainly according to the amount of halogen used. In particular, a halogen equivalent yields a monodemethylated product, and 2 or more halogen equivalents yields a predominantly didemethylated product. If desired, the preparation of the didemethylated product can also be based on the already monodemethylated product.

The mono- or didemethylated erythromycin A can be converted in a known manner by mild acid treatment to the corresponding mono- or didemethylated 8,9-anhydroerythromycin-A-6,9-hemiketal of formula IV

wherein it is hydrogen or methyl. Hemiketal formation can be achieved, for example, by treatment with acetic acid or dilute mineral acid at temperatures between room temperature and about 50 ° C.

In the compounds of formula IV, the ring constriction of the 14-membered lactone ring of the erythromycin structure to a 12-membered lactone ring can be accomplished by a known method by intramolecular translactonization to give the corresponding compound of formula II.

The compounds of the formula IV are heated in a manner known per se in the lower alcohol in the presence of a base, for example to temperatures between 40 ° C and 70 ° C, preferably to the boiling point of the reaction mixture. Suitable bases are, in particular, alkali metal carbonates, but also organic bases such as tertiary amines, especially lower alkyl tertiary amines. This narrowing of the circle does not change the configuration of the chiral centers.

The novel compounds of formula I and their physiologically tolerable acid addition salts have interesting pharmacological properties, in particular motilin-agonist properties stimulating the motility of the gastrointestinal tract. They have no antibiotic effects and have a highly selective affinity for motilin receptors, whereas they do not show virtually relevant affinity for other receptors in the gastrointestinal tract, such as adrenaline, acetylcholine, histamine, dopamine or serotonin receptors, in the motilin-agonist effective dose ranges.

In order to ensure the controlled digestion of food intake, the autonomous nervous system and the gastrointestinal tract hormones work together in a healthy state to induce controlled withdrawal of the gastrointestinal tract not only after intake, but also in the empty gastrointestinal tract. Motilin is a known gastrointestinal peptide hormone that stimulates the motility of the gastrointestinal tract and induces coordinated motility throughout the gastrointestinal tract in the fasted state as well as upon food intake.

The compounds of formula I exhibit motilin-like physiological effects by becoming effective as agonists for motilin receptors. Thus, the compounds of formula I exhibit significant stimulatory effects in the range of the stomach and intestines and on the lower gastrointestinal sphincter. In particular, they affect the acceleration of gastric emptying and the prolonged increase in the resting tone of Oesophagus Sphincter. Because of their motilin-like effect profile, the agents are useful in the treatment of disease states related to gastrointestinal motility disorders and / or gastric feed backflow from the stomach to the digestive tube. Compounds of formula I are thus indicated, for example, in gastric paresis of various origins, gastric emptying disorders and gastrooesophagal reflux, dyspepsia, colonial anomalies, such as in irritable bowel syndrome (IBS) and postoperative motility disorders, eg, intestinal obstruction (ileum).

Gastrointestinally effective properties of the compounds of formula I can be demonstrated by conventional in vitro and in vivo pharmacological test methods.

Description of test methods

1. Determination of binding ability of test substances to motilin receptors

The affinity of the compounds of formula I as well as the motilin receptors is measured in vitro on a rabbit hemtrate tissue hemogenate fraction. The suppression of radiolabeled iodinated motilin from motilin-receptor binding by the test substances is determined.

Receptor binding studies are performed according to a modified method by Borman et al. (Peptides regulators "125 (1986), 143-153). In the production of iodine-labeled motilin, motilin is iodinated in a manner known per se, e.g.

analogously by Bloom et al. (Scand. J. Gastroenterol.

(1976), 47-52) enzymatically using lactoperoxidase.

To obtain the tissue homogenate fraction used herein, which is prepared from rabbit anthra, the antrum is dissected and cut into small pieces and homogenized in a 10-fold volume of homogenization buffer solution (50 mM Tris-HCl buffer, 250 mM sucrose, 25 mM KCl, 10 mM MgCl 2, pH 7.4) with the addition of inhibitors (1 mM iodoacetamide, 1 µM peppstatin, 0.1 mM methylsulfonyl fluoride, 0.1 g / l trypsin inhibitor, 0.25 g / l bactracin) with a 15 second homogenizer at 1500 rpm. The homogenate is then centrifuged at 1000 g for 15 minutes, the residue is washed four times with a homogenizing buffer solution and finally suspended in 0.9% sodium chloride solution (in a volume corresponding to 5 times the anthra mass). The tissue fraction thus obtained, referred to as the crude membrane preparation, is used in the assay.

For the binding experiment with 200 µl of crude membrane fraction (0.5-1 mg protein) in 400 µl of buffer solution A (50 mM Tris-HCl buffer, 1.5% BSA, 10 mM MgCl 2, pH 8.0 Dilute 100 µl of iodinated motilin in buffer solution B (10 mM Tris-HCl buffer, 1% BSA, pH 8) (final concentration 50 µM) and incubate for 60 minutes at 30 ° C. The reaction is stopped by adding 3.2 ml of cold buffer solution B and bound and unbound motilin is separated by centrifugation (1000 g, 15 minutes). The pellet residue is washed with buffer solution B and counted in a gamma counter. Extrusion studies are performed by adding increasing amounts of test substance to the incubation environment. Aqueous solutions are used as solutions of the test substances and are prepared by appropriate dilution of the stock solution (60 x 10 molar). The poorly soluble test substances are first dissolved in 60% ethanol and diluted with water so that the ethanol concentration in the test solution does not exceed 1.6% by volume. From the measured values obtained, the concentration which causes 50% inhibition of the specific binding of iodinated motilin to motilin receptors is determined as ΙΟ ^ θ of the individual test substance. From this concentration the corresponding value ρΙΟ ^ θ is calculated. This method determined ρ látku ^ θ as 8.32 for the substance in Example 1.

2. Determination of in vivo effect of substances on gastric emptying rate

The gastric emptying rate is determined on beagle dogs which, prior to the experiment, introduce an oesophagus fistula and implant the duodenal cannula, which is done operatively. After 15 minutes of duodenal administration of the test substances, fasting, vigorous dogs are administered 285 g of a semi-solid caloric test meal via an oesophagus fistula. The contents emptied by the stomach are collected through the duodenal cannula at 15 minute intervals. From the amount of stomach contents collected, the time span during which the stomach is emptied by 50% is calculated. This time span is given as a measure of gastric emptying.

In this test model, the compound of Example 1 showed a clear stimulation of gastric emptying at a dose of 0.46 µM / kg. The time required for 50% gastric emptying was reduced from 46 minutes in the control group of animals to 27 minutes in the test animals.

3. Determination of in vivo effect of compounds on resting tone of Oesophagus Sphincter

This determination is performed on trained, alert, fasting beagle dogs, which are introduced after one oesophagus fistula and one duodenal cannula prior to the experiment.

The lower Oesophagus Spincter pressure is measured using a perfused catheter system with a side orifice connected to a pressure transducer and recorder. Katheter is guided through the oesophageal fistula into the stomach and then slowly pulled back manually (= stretching manometry). A peak is recorded as the part of the catheter with the side opening passes through the high pressure zone of the lower Oesophagus Spincter. From this peak, the pressure in mm Hg is determined.

In this way, the baseline pressure of Oesophagus Spincter is first determined as a control value. Subsequently, the intraduodenally test substance is applied and after 15 minutes the pressure on the lower Oesophagus Spincter is measured at 2 minute intervals for 46 minutes. The pressure increase after administration of the test substance is calculated compared to the predetermined basal pressure.

In this test, the basal pressure of Oesophagus Spincter more than doubled due to a dose of 0.251 µM / kg of the compound of Example 1. This effect persisted for a total test time of 45 minutes.

Because of their effects in the gastrointestinal tract, the compounds of formula I are suitable for use in gastroenterology as medicaments for larger mammals, particularly humans, for the prophylaxis and treatment of motility disorders of the gastrointestinal tract.

The doses to be used may vary greatly and vary according to the nature and type of condition to be treated and the application. For example, transparent formulations generally contain less active ingredients than oral preparations. In general, however, dosage forms containing from 5 to 5 mg of active ingredient are suitable for applications in larger mammals, especially humans

200 mg per single dose.

As medicaments, the compounds of formula I may be present with conventional pharmaceutical excipients in galenical preparations, e.g. tablets, capsules, suppositories or solutions. These galenic formulations may be prepared according to methods known per se using conventional solid carriers such as milk sugar, starch or talc or liquid diluents such as water, fatty oils or liquid paraffins, using conventional excipients, e.g. for compressing tablets, solubilizers or preservatives.

The following examples are intended to illustrate the invention in further detail without limiting its scope.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 [2R, 3R (2R ', 3R'), 6R, 7S, 8S, 9R, 1R] -3- (2 ', 3'-dihydroxypent 2'-yl) -7- (2,6-dideoxy- 3-C-methyl-3-O-methyl-c (-L-ribohexpyranosyl) -oxy] -9- 3,4,6-trideoxy-3- (N-methyl-Nisopropylamino) -β-D-xylohexopyranosyl) - oxy] -2,6,8,10,12pentamethyl-4,13-dioxabicyclo (3.2.1) tridec-12-en-5-one (= compound of formula I, R ³ = methyl)

A) Preparation of N-desmethylerythromycin A g erythromycin A (= 27.2 mmol) and 11.2 g (=

136.2 mmol) of sodium acetate are dissolved in 200 ml of methanol / water 8: 2. The solution was heated to 47 ° C. Then 6.9 g (= 136.2 mmol) of iodine are added. The pH is maintained at 8-9 by addition of dilute aqueous sodium hydroxide solution. After 3 hours, the reaction mixture is poured into a mixture of 1 liter of water and 20 ml of ammonium hydroxide solution. The reaction mixture is extracted with ethyl acetate and the organic extract is washed with water containing ammonium hydroxide and then concentrated. The crude product remaining after removal of the solvent was recrystallized with 50: 3 acetone / ammonium hydroxide solution. M.p. 143-148 ° C.

B) Preparation of N-desmethyl-8,9-anhydroerythromycin-A-6,9-hemiketal (= compound of formula IV, R ^x = methyl) g of the product obtained under A) is dissolved in 110 ml of glacial acetic acid and stirred for 1 hour at room temperature. The reaction mixture is then treated dropwise into 400 ml of concentrated ammonium hydroxide solution under ice-cooling. The reaction mixture is extracted with ethyl acetate, the organic extract is washed with water and the solvent is stripped off. The crude product remaining as a residue was recrystallized first from ether and then from methanol. 14 g of pure product are obtained with a melting point of 145 ° C.

C) Preparation of [2 ^{R 3 R} <2R> ³ X '>' 6R, 7S, 8S, 9R, 10R] -3- (2 ', 3') -dihydroxypent-2'-yl) -7- £ (2 6-dideoxy-3-C-methyl-3-methyl-α (-L-ribo-hexpyranosyl) -oxy] -9- (3,4,6-trideoxy-3-methylamino-β-D-xylo-hexopyranosyl) -oxy] -2,6,8,10,12pentamethyl-4,13-dioxabicyclo Q8.2.1] tridec-12-en-5-one (= compound of formula II, R 1 -methyl)

9.4 g (= 13.4 mmol) of the product obtained in (B) are refluxed with 1.9 g (= 13.4 mmol) of potassium carbonate in methanol for 2.5 hours. The reaction mixture is concentrated, diluted with water and extracted with ethyl acetate. The crude product remaining after solvent removal is recrystallized from isopropanol. 7.1 g of pure product are obtained with a melting point of 199 to 200 ° C, optical rotation 7 7 °: - 31.6 ° ⁽ = = ¹ '"> ^ethano1 >

D) Preparation of the title compound g (= 2.8 mmol) of the product obtained according to paragraph C) is dissolved in methanol and the pH of the solution is adjusted to 4 by adding dilute hydrochloric acid solution to the solution. calcium aluminum silicate, pore diameter 4%), excess acetone and 0.4 g (= 6.4 mmol) of sodium cyanoborohydride.

The reaction mixture was stirred for 12 hours. When separating the mixture, the molecular sieve is filtered off, the filtrate is concentrated, diluted with water and extracted with ethyl acetate. The crude product remaining after concentration of the ethyl acetate extract was purified by column chromatography over silica gel (ethyl acetate / methanol 95: 5 as eluant). 1.4 g of the title compound of melting point 130 DEG-134 DEG C., optical rotation, is obtained

C «] D ° ^{- 32 '8} ° Example 2 (2R, 3R (2R, 3R), 6R t, j, 7S, 8S, 9R, 10R] -3- (2', 3 ' -dihydro ^ ent -2'-yl) -7- [2,6-dideoxy-3-C-methyl-3-O-methyl-of-L-ribohexpyranosyl) oxy] -9 - [(3,4,6-trideoxy) -3- (N-methyl-Nisopropylamino) -BD-xylohexopyranosyl) oxy] -2,6,8,10,12-pentamethyl-4,13-dioxabicyclo [8.2.1] tridec-12-en-5-one (= compound of formula I, R 1 = methyl)

A) Preparation of N-desmethylerythromycin A g erythromycin A and 4.7 g sodium acetate (x 3 L 40) were dissolved in 200 ml methanol / water 8: 2.

1.75 g of iodine was added to the solution, and the reaction mixture was then irradiated at room temperature for 20 minutes with a quartz lamp. Then half of the solvent was evaporated and the remaining reaction mixture was poured into a mixture of 140 ml of water and 10 ml of ammonia.

The reaction mixture was extracted three times with 20 ml of methyl t-butyl ether each time. The ether extract was separated and the ether partially evaporated. The reaction product is then crystallized and recrystallized from acetone. 2 g of N-desmethylerythromycin A are obtained.

B) To prepare N-desmethyl-8,9-anhydroerythromycin-A-b, 9-hemiketal (= compound of formula IV, = methyl), 2 g of the product obtained in A) was treated as described in Example 1 B). 2.3 g of hemiketal are obtained in the form of an amorphous solid.

0) For the manufacture of [2R, 3R (2R ', 3R'), 6R, 7S, 8S, 9R, 10R] -3- (2 ', 3'-dihydroxypent-2'-yl) -7- (2', 3'-dihydroxypent-2'-yl) 6-dideoxy-3-C-methyl-3-methyl-α-L-ribo-hexpyranosyl) -oxy] -9- (3,4,6-trideoxy-3-methylamino-β-xylo-hexopyranosyl) -oxy] - 2,6,8,10,12pentamethyl-4,13-dioxabicyclo [8.2.1] tridec-12-en-5-one (= compound of formula II, R 1 = methyl), 2.3 g of the above product is used, as described in Example 1C). The crude product obtained is recrystallized from ethyl acetate. 1.3 g of pure product are obtained, m.p. 199-202 ° C.

D) 1.3 g of the product obtained above were added to a mixture of 26 ml of acetone and 0.11 ml of acetic acid. 0.6 g of sodium triacetoxyborohydride was added portionwise under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 4 hours. Two-thirds of the solvent is evaporated and the residue is diluted with 40 ml of ethyl acetate. 65 ml of saturated sodium hydrogen carbonate solution are added with vigorous stirring. The organic phase is separated from the clear solution formed and the aqueous phase is washed once more with 20 ml of ethyl acetate. The combined organics were washed with 13 mL of water and dried over sodium sulfate. The solvent is evaporated, the residue is taken up in 20 ml of toluene, which is again evaporated. The crude product obtained is purified by filtration through a column of alumina (25 g of Al2 O4, activity level II / III), eluting with ethyl acetate. Then the solvent was evaporated and the residue was dissolved in boiling ethyl acetate.

Then n-hexane is added until the mixture becomes cloudy. The product is crystallized in the cold. The formed crystals were filtered off under reduced pressure and washed with n-hexane. 0.8 g of the title compound of melting point 128-135 ° C is obtained.

Ε) To convert to its acetate, use 1 g (= 1.3 mmol) of the title compound, which is dissolved in methanol and combined with 0.08 mL (= 1.3 mmol) of glacial acetic acid. Thereafter, the solvent is stripped off under reduced pressure and the resulting acetate is dried. The melting point of the title compound is 145-150 ° C. Optical Rotation Value [α] D 20: -30.8 ° (c = 1, methanol).

Example I

Tablets are produced with the following composition for one tablet:

[2R, 3R (2R ', 3R'), 6R, 7S, 8S, 9R, 1R] -3 (2 ', 3'-dihydroxypent-2'-yl) -7 - [(2,6dideoxy-3-C-) - methyl-3-O-methyl-o (-Libro-hexpyranosyl) -oxy] -9 - [(3,4,6-trideoxy-3- (N-methyl-N-isopropylamino) -β-D-xylo-hexopyranosyl) oxy] -2,6,8,10,12-pentamethyl-4,13dioxabicyklo [_8.2. l] tridec-12-en-5-one (= compound of formula I, R ¹ = methyl) 20 mg cornstarch 60 mg of milk sugar 135 mg gelatin (as a 10% solution) 6 mg

The active substance, maize starch and milk sugar are concentrated with a 10% gelatin solution. The paste is ground and the resulting granulate is placed on a suitable sheet and dried at 45 ° C. The dried granulate is passed through a grinding machine and mixed in a mixer with the following other ingredients: talc 5 mg magnesium stearate 5 mg corn starch and then compressed into tablets weighing 240 mg.

mg

Claims (5)

1. [2R, 3R (2R ', 3R'), 6R, 7S, 8S, 9R, 10R] -3- (2 ', 3'-dihydroxypent-2-yl) -2,6,8,10,12- Pentamethyl-4,13-dioxabicyclo {η 8.2.1. tridec-12-en-5-one derivatives of formula I R ^l in which R is methyl or hydrogen, and their physiologically tolerable stable acid addition salts. Compounds according to claim 1, wherein R 1 is methyl. A medicament comprising a pharmacologically effective amount of a compound according to claim 1 and conventional excipients and / or carriers. 4. A process for the preparation of derivatives of 2R, 3R (2R ', 3R '), 6R, 7S, 8S, 9R, 1R, 3- (2 ', 3'-dihydroxypent-2'-yl) -2,6,8,10 12,1-pentamethyl-4,13-dioxabicyclo [8.2.1] tridec-12-en-5-one of formula I B? wherein R ¹ is methyl or a hydrogen atom, and their stable physiologically tolerable acid addition salts, characterized in that the derivative £ 2 R, 3 R (2 R, 3 R), 6 R, 7 S, 8 S, 9 R, 10 R] -3 - (2 ', 3'-dihydroxypent-2-yl) -2,6,8,10,12-pentamethyl-4,13-dioxabicyclo-8.2. 1] tridec-12-en-5-one of formula II R ¹ I (ii) introducing an isopropyl radical, and, if necessary, the obtained compound of formula I in which R represents a hydrogen atom, introducing a methyl radical R, or in the resulting compound of formula I wherein R ¹ is methyl, the methyl the residue R @ ¹ is cleaved and, if desired, the free compounds of the formula I are converted into their stable acid addition salts or the addition salts are converted into the free compounds of the formula I. 5. [2R, 3R (2R ', 3R'), 6R, 7S, 8S, 9R, 1R] -3 (2 ', 3'-dihydroxypent-2'-yl) -2,6,8,10,12 derivatives -pentamethyl-4,13-dioxabicyclo [8.2.1] tridec-12-en-5-one of the general formula II h ₃ c (II) wherein R represents methyl or hydrogen.